Traumatic brain injury (TBI) is a significant U.S. health concern, with over 1.7 million new cases each year. Loss of brain circuitry underlies persistent cognitive deficits suffered by its victims, with axonal damage as a major contributor. Using the injured corpus callosum (CC) as a model, we have shown that postinjury change in matrix metalloproteinases (MMPs) is correlated with distinct myelinated and unmyelinated fiber pathology. MMPs are critical modulators of brain extracellular matrix (ECM) which affect axonal integrity. We found that CC gelatinases MMP2 and 9 peak in activity at different postinjury intervals which are marked by reactive glial response. We also observed that this MMP activity was temporally correlated with unmyelinated axon pathology. Treatment with neuroprotective compounds FK-506 and minocycline resulted in selective, time- dependent reduction of this gelatinase activity and reduced deficits in CC compound action potentials(CAPs). Pilot microarray studies revealed that osteopontin (OPN), a cytokine secreted into the ECM and reciprocally linked to MMP function, was significantly upregulated in injured CC. From these data we hypothesize that gelatinase response to traumatic axonal injury is mediated through acute activation of OPN within reactive glia. We also posit that the time course and glial role in this pathway will differ between unmyelinated and myelinated fibers. To test these hypotheses, the following aims will be explored in the fluid percussion model of TBI : 1) to document OPN/MMP2,9 during axonal injury within fiber environments enriched in unmyelinated (ON, olfactory nerve) and myelinated fibers (IC, internal capsule), and determine if OPN KO and MMP9KO alters these changes, 2) to dissect cell specific OPN/MMP2,9 interaction in vitro using primary CC and ON glial cultures, and 3) to test whether OPNKO or MMPKO alters efficacy of axonal neuroprotective drugs FK-506 and minocycline, then determine if combining optimal drug and OPN/MMP9 manipulation alters functional or structural outcome in the rat model of FPTBI. These studies are likely to identify novel options for regional and fiber targeted therapy in patients suffering from axonal damage after TBI.